This invention relates to novel ester derivatives of prostaglandin E.sub.2 analogs (hereinafter identified as "PGE.sub.2 " analogs), including the 16-alkyl, 16-fluoro, 16-phenoxy, and phenyl-substituted analogs, and their 15-epimers, and their racemic forms, and to processes for producing them.
PGE.sub.2 is represented by the formula: ##STR1## A systematic name for PGE.sub.2 is 7-{3.alpha.-hydroxy-2.beta.-[(3S )-3-hydroxy-trans-1-octenyl] -5-oxo-1.alpha.-cyclopentyl}-cis-5-heptenoic acid. PGE.sub.2 is known to be useful for a variety of pharmacological and medical purposes, for example labor induction and abortion in pregnant animals, including humans, menstrual regulation in both pregnant and non-pregnant animals, including humans, reduction and control of gastric secretion, and as a hypotensive agent to reduce blood pressure in mammals, including humans. See Bergstrom et al., Pharmacol. Rev. 20, 1 (1968) and references cited therein. As to racemic PGE.sub.2, see for example W. P. Schneider, Chem. Commun. 304 (1969).
The 16-alkyl and 16-fluoro analogs of PGE.sub.2 and their 15-epimers are represented by the formula: ##STR2## wherein Y is ##STR3## following the usual convention wherein broken line attachment of hydroxy to the side chain at carbon 15 indicates the natural or ".alpha." configuration and solid line attachment of hydroxy indicates the epi or ".beta." configuration. In certain instances the "S" and "R" nomenclature are used. See Nugteren et al., Nature 212, 38 (1966) and Cahn, J. Chem. Ed. 41, 116 (1964).
In formula ll C.sub.g H.sub.2g is alkylene of one to 9 carbon atoms, inclusive, with one to 5 carbon atoms, inclusive, in the chain between --CR.sub.1 R.sub.2 -- and terminal methyl; and R.sub.1 and R.sub.2 are hydrogen, methyl, ethyl, or fluoro, being the same or different, with the proviso that at least one of R.sub.1 and R.sub.2 is other than hydrogen, and with the further proviso that R.sub.2 is fluoro only when R.sub.1 is hydrogen or fluoro.
The 16-alkyl and 16-fluoro analogs of PGE.sub.2 and their 15-epimers in their optically active and racemic forms are known. See for example South African Patent No. 72/1936, Derwent Farmdoc No. 71483T; and South African Patent No. 73/2244, Derwent Farmdoc No. 69717U. These analogs are also useful for the above-described pharmacological purposes.
The 16-phenoxy and phenyl-substituted analogs of PGE.sub.2 and their 15-epimers are represented by the formula: ##STR4##
In formula lll, R.sub.3 and R.sub.4 are hydrogen, methyl, or ethyl; T is alkyl of one to 4 carbon atoms, inclusive, fluoro, chloro, trifluoromethyl, or --OR.sub.5, wherein R.sub.5 is hydrogen or alkyl of one to 4 carbon atoms, inclusive, and s is zero, 1, 2, or 3, with the proviso that not more than two T's are other than alkyl; Y is ##STR5## and Z represents an oxa atom (--O--) or C.sub.j H.sub.2j, wherein C.sub.j H.sub.2j is a valence bond or alkylene of 1 to 9 carbon atoms, inclusive, substituted with zero, 1, or 2 fluoro, with 1 to 6 carbon atoms, inclusive, between --CR.sub.3 R.sub.4 -- and the ring.
The 16-phenoxy and phenyl-substituted analogs of PGE.sub.2 and their 15-epimers in their optically active and racemic forms are known. See for example South African Patent No. 73/2818, Derwent Farmdoc No. 73279U; and British Specification No. 1,324,737, Derwent Farmdoc No. 31279T.
Esters of the above compounds are known, wherein the hydrogen atom of the carboxyl group is replaced by a hydrocarbyl or substituted hydrocarbyl group. Among these are the methyl ester of 16-methyl-PGE.sub.2, the methyl ester of 16,16-dimethyl-PGE.sub.2 (A. Robert et al., Gastroenterology 64, 790 (1973)); the phenyl and alkyl-phenyl esters of 16-fluoro- and 16,16-difluoro-PGE.sub.2 (South African Patent No. 73/2244); the phenyl and alkyl-phenyl esters of 16-phenoxy-PGE.sub.2 (South African Patent No. 73/2818); and the phenyl and alkyl-phenyl esters of phenyl-substituted PGE.sub.2 (British Specification No. 1,324,737).